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Analysis of the Role of Negative T Cell Costimulatory Pathways in CD4 and CD8 T Cell-Mediated Alloimmune Responses In Vivo

2005; American Association of Immunologists; Volume: 174; Issue: 11 Linguagem: Inglês

10.4049/jimmunol.174.11.6648

1550-6606

Toshiro Ito, Takuya Ueno, Michael R. Clarkson, Xueli Yuan, Mollie Jurewicz, Hideo Yagita∥, Miyuki Azuma, Arlene H. Sharpe, Hugh Auchincloss, Mohamed H. Sayegh, Nader Najafian,

Cancer Immunotherapy and Biomarkers

Abstract Negative costimulatory signals mediated via cell surface molecules such as CTLA-4 and programmed death 1 (PD-1) play a critical role in down-modulating immune responses and maintaining peripheral tolerance. However, their role in alloimmune responses remains unclear. This study examined the role of these inhibitory pathways in regulating CD28-dependent and CD28-independent CD4 and CD8 alloreactive T cells in vivo. CTLA-4 blockade accelerated graft rejection in C57BL/6 wild-type recipients and in a proportion of CD4−/− but not CD8−/− recipients of BALB/c hearts. The same treatment led to prompt rejection in CD28−/− and a smaller proportion of CD4−/−CD28−/− mice with no effect in CD8−/−CD28−/− recipients. These results indicate that the CTLA-4:B7 pathway provides a negative signal to alloreactive CD8+ T cells, particularly in the presence of CD28 costimulation. In contrast, PD-1 blockade led to accelerated rejection of heart allografts only in CD28−/− and CD8−/−CD28−/− recipients. Interestingly, PD-1 ligand (PD-L1) blockade led to accelerated rejection in wild-type mice and in all recipients lacking CD28 costimulation. This effect was accompanied by expansion of IFN-γ-producing alloreactive T cells and enhanced generation of effector T cells in rejecting allograft recipients. Thus, the PD-1:PD-L1 pathway down-regulates alloreactive CD4 T cells, particularly in the absence of CD28 costimulation. The differential effects of PD-1 vs PD-L1 blockade support the possible existence of a new receptor other than PD-1 for negative signaling through PD-L1. Furthermore, PD-1:PD-L1 pathway can regulate alloimmune responses independent of an intact CD28/CTLA-4:B7 pathway. Harnessing physiological mechanisms that regulate alloimmunity should lead to development of novel strategies to induce durable and reproducible transplantation tolerance.